Genetic Influences on the Amount of Cell Death in the Neural Tube of BXD Mice Exposed to Acute Ethanol at Midgestation.
Alcohol Exposure at Embryonic Day 9.5
Apoptosis
BXD Strains
FASD
Genetics
Journal
Alcoholism, clinical and experimental research
ISSN: 1530-0277
Titre abrégé: Alcohol Clin Exp Res
Pays: England
ID NLM: 7707242
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
09
08
2018
accepted:
19
12
2018
pubmed:
28
12
2018
medline:
12
5
2020
entrez:
28
12
2018
Statut:
ppublish
Résumé
Fetal alcohol spectrum disorders (FASD) have a strong genetic component although the genes that underlie this are only beginning to be elucidated. In the present study, one of the most common phenotypes of FASD, cell death within the early developing neural tube, was examined across a genetic reference population in a reverse genetics paradigm with the goal of identifying genetic loci that could influence ethanol (EtOH)-induced apoptosis in the early developing neural tube. BXD recombinant inbred mice as well as the parental strains were used to evaluate genetic differences in EtOH-induced cell death after exposure on embryonic day 9.5. Dams were given either 5.8 g/kg EtOH or isocaloric maltose-dextrin in 2 doses via intragastric gavage. Embryos were collected 7 hours after the initial exposure and cell death evaluated via TUNEL staining in the brainstem and forebrain. Genetic loci were evaluated using quantitative trait locus (QTL) analysis at GeneNetwork.org. Significant strain differences were observed in the levels of EtOH-induced cell death that were due to genetic effects and not confounding variables such as differences in developmental maturity or cell death kinetics. Comparisons between the 2 regions of the developing neural tube showed little genetic correlation with the QTL maps exhibiting no overlap. Significant QTLs were found on murine mid-chromosome 4 and mid-chromosome 14 only in the brainstem. Within these chromosomal loci, a number of interesting candidate genes were identified that could mediate this differential sensitivity including Nfia (nuclear factor I/A) and Otx2 (orthodenticle homeobox 2). These studies demonstrate that the levels of EtOH-induced cell death occur in strain- and region-dependent manners. Novel QTLs on mouse Chr4 and Chr14 were identified that modulate the differential sensitivity to EtOH-induced apoptosis in the embryonic brainstem. The genes underlying these QTLs could identify novel molecular pathways that are critical in this phenotype.
Sections du résumé
BACKGROUND
Fetal alcohol spectrum disorders (FASD) have a strong genetic component although the genes that underlie this are only beginning to be elucidated. In the present study, one of the most common phenotypes of FASD, cell death within the early developing neural tube, was examined across a genetic reference population in a reverse genetics paradigm with the goal of identifying genetic loci that could influence ethanol (EtOH)-induced apoptosis in the early developing neural tube.
METHODS
BXD recombinant inbred mice as well as the parental strains were used to evaluate genetic differences in EtOH-induced cell death after exposure on embryonic day 9.5. Dams were given either 5.8 g/kg EtOH or isocaloric maltose-dextrin in 2 doses via intragastric gavage. Embryos were collected 7 hours after the initial exposure and cell death evaluated via TUNEL staining in the brainstem and forebrain. Genetic loci were evaluated using quantitative trait locus (QTL) analysis at GeneNetwork.org.
RESULTS
Significant strain differences were observed in the levels of EtOH-induced cell death that were due to genetic effects and not confounding variables such as differences in developmental maturity or cell death kinetics. Comparisons between the 2 regions of the developing neural tube showed little genetic correlation with the QTL maps exhibiting no overlap. Significant QTLs were found on murine mid-chromosome 4 and mid-chromosome 14 only in the brainstem. Within these chromosomal loci, a number of interesting candidate genes were identified that could mediate this differential sensitivity including Nfia (nuclear factor I/A) and Otx2 (orthodenticle homeobox 2).
CONCLUSIONS
These studies demonstrate that the levels of EtOH-induced cell death occur in strain- and region-dependent manners. Novel QTLs on mouse Chr4 and Chr14 were identified that modulate the differential sensitivity to EtOH-induced apoptosis in the embryonic brainstem. The genes underlying these QTLs could identify novel molecular pathways that are critical in this phenotype.
Identifiants
pubmed: 30589433
doi: 10.1111/acer.13947
pmc: PMC6410727
mid: NIHMS1003881
doi:
Substances chimiques
Ethanol
3K9958V90M
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
439-452Subventions
Organisme : NIAAA NIH HHS
ID : F31 AA026498
Pays : United States
Organisme : Canadian Network of Centres of Excellence
Pays : International
Organisme : NIAAA NIH HHS
ID : R01 AA023508
Pays : United States
Organisme : NeuroDevNet
Pays : International
Informations de copyright
© 2018 by the Research Society on Alcoholism.
Références
Neurotoxicol Teratol. 1995 Jul-Aug;17(4):437-43
pubmed: 7565490
Behav Genet. 1991 Mar;21(2):99-116
pubmed: 2049054
J Pediatr. 1975 Dec;87(6 Pt 1):963-7
pubmed: 1185405
Alcohol Drug Res. 1987;7(5-6):423-41
pubmed: 3304313
Dev Dyn. 2007 Feb;236(2):613-31
pubmed: 17200951
J Pharmacol Exp Ther. 2018 Mar;364(3):420-432
pubmed: 29259041
Nat Neurosci. 2004 May;7(5):485-6
pubmed: 15114364
Glia. 2015 Oct;63(10):1694-713
pubmed: 25856413
Physiol Genomics. 2015 Aug;47(8):308-17
pubmed: 25991709
Neuro Oncol. 2017 Apr 1;19(4):524-534
pubmed: 27994064
Neuroinformatics. 2003;1(4):299-308
pubmed: 15043217
Alcohol Clin Exp Res. 2001 Oct;25(10):1523-35
pubmed: 11696674
Biol Open. 2014 Jul 25;3(8):741-58
pubmed: 25063196
PLoS One. 2017 Jun 2;12(6):e0178689
pubmed: 28575045
Lancet. 1973 Jun 9;1(7815):1267-71
pubmed: 4126070
Teratology. 1980 Aug;22(1):71-5
pubmed: 7003793
Alcohol. 1997 Jul-Aug;14(4):389-95
pubmed: 9209555
Alcohol Clin Exp Res. 1998 Apr;22(2):345-51
pubmed: 9581639
Alcohol Clin Exp Res. 2011 Jul;35(7):1293-304
pubmed: 21410487
Toxicol Lett. 2017 Nov 5;281:53-64
pubmed: 28919490
Brain Res. 2006 Dec 6;1123(1):216-225
pubmed: 17078933
Alcohol Clin Exp Res. 2012 Aug;36(8):1340-54
pubmed: 22413943
Psychopharmacology (Berl). 1991;104(4):413-24
pubmed: 1780413
Psychopharmacology (Berl). 1995 Jul;120(1):28-41
pubmed: 7480533
Trends Pharmacol Sci. 1992 May;13(5):212-9
pubmed: 1604714
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7
pubmed: 15075390
Brain Res Dev Brain Res. 2002 Feb 28;133(2):115-26
pubmed: 11882342
Brain Res. 2009 Aug 18;1285:30-41
pubmed: 19555672
Neuroinformatics. 2003;1(4):343-57
pubmed: 15043220
JAMA. 2018 Feb 6;319(5):474-482
pubmed: 29411031
Brain Res. 2012 Jun 6;1458:18-33
pubmed: 22560501
PLoS One. 2012;7(4):e33575
pubmed: 22511924
Alcohol Health Res World. 1997;21(4):287-97
pubmed: 15706739
Reprod Toxicol. 2011 Sep;32(2):227-34
pubmed: 21658441
Dis Model Mech. 2013 Jul;6(4):977-92
pubmed: 23580197
Alcohol Clin Exp Res. 2015 Feb;39(2):221-31
pubmed: 25664654
Autophagy. 2012 Feb 1;8(2):165-76
pubmed: 22248718
Am J Med Genet. 1992 Sep 15;44(2):168-76
pubmed: 1456286
Neurotoxicol Teratol. 2013 Sep-Oct;39:77-83
pubmed: 23911654
Stem Cells. 2007 May;25(5):1096-103
pubmed: 17234991
Alcohol Clin Exp Res. 2016 Jun;40(6):1154-65
pubmed: 27122355
Brain Res Dev Brain Res. 2000 Jan 3;119(1):75-83
pubmed: 10648874
Neurotoxicol Teratol. 1990 May-Jun;12(3):231-7
pubmed: 2196422
Neurobiol Dis. 2002 Mar;9(2):205-19
pubmed: 11895372
PLoS One. 2017 Jul 19;12(7):e0180873
pubmed: 28723918
Neurogenetics. 2016 Apr;17(2):91-105
pubmed: 26780340
BMC Genet. 2004 Apr 29;5:7
pubmed: 15117419
J Neurosci. 2005 Jul 13;25(28):6533-8
pubmed: 16014714
J Neurosci. 2001 Feb 15;21(4):1292-301
pubmed: 11160400
J Neurosci. 2013 Apr 10;33(15):6350-66
pubmed: 23575834
Mol Pharmacol. 2015 Jul;88(1):161-70
pubmed: 25715797
Int J Dev Neurosci. 1992 Aug;10(4):273-9
pubmed: 1414440
Alcohol. 2017 Feb;58:139-151
pubmed: 28027852
Dev Med Child Neurol. 1980 Aug;22(4):525-45
pubmed: 7409345
Neurosci Lett. 2015 Jun 26;598:73-8
pubmed: 25982323
Teratology. 1984 Oct;30(2):281-90
pubmed: 6495228
PLoS One. 2017 Mar 21;12(3):e0173890
pubmed: 28323865
Brain Res. 1999 Jan 30;817(1-2):13-8
pubmed: 9889302
J Neurosci. 1993 Jan;13(1):285-99
pubmed: 8423474
Front Genet. 2014 Jul 15;5:203
pubmed: 25076964
Neurobiol Dis. 2009 Jan;33(1):111-8
pubmed: 18992344
PLoS One. 2014 Aug 05;9(8):e104172
pubmed: 25093331
Brain Res Dev Brain Res. 2002 Sep 20;138(1):45-59
pubmed: 12234657